Akt-dependent Activation of mTORC1 Complex Involves Phosphorylation of mTOR (Mammalian Target of Rapamycin) by IκB Kinase α (IKKα)

The serine/threonine protein kinase Akt promotes cell survival, growth, and proliferation through phosphorylation of different downstream substrates. A key effector of Akt is the mammalian target of rapamycin (mTOR). Akt is known to stimulate mTORC1 activity through phosphorylation of tuberous sclerosis complex 2 (TSC2) and PRAS40, both negative regulators of mTOR activity. We previously reported that I kappa B kinase alpha (IKK alpha), a component of the kinase complex that leads to NF-kappa B activation, plays an important role in promoting mTORC1 activity downstream of activated Akt. Here, we demonstrate IKK alpha-dependent regulation of mTORC1 using multiple PTEN null cancer cell lines and an animal model with deletion of IKK alpha. Importantly, IKK alpha is shown to phosphorylate mTOR at serine 1415 in a manner dependent on Akt to promote mTORC1 activity. These results demonstrate that IKK alpha is an effector of Akt in promoting mTORC1 activity.